Most human disease has a genetic basis in cause, susceptibility, or resistance. However, the genetic architectures for most disease phenotypes are only poorly understood and architectures of genetic plasticity - the ability to modify genetic networks to favor one trait without adversely affecting other traits that rely on the same underlying genes - are understood almost not at all. We have previously demonstrated through positional identification of a novel wild-derived modifier gene in mice one instructive example. The Mvb1 locus attenuates the effects of retroviral insertion mutations without apparent disruption of the host gene expression program. Indeed, the variant we identified shows hallmarks of positive selection in wild populations, consistent with a role in innate immunity to a pathogen. This competing renewal application continues our work to understand the mechanisms of genetic suppression mediated by alleles of the Nxf1 gene at the Mvb1 locus. This renewal supports development of new mouse models for human disease and therapy based on modulating gene expression levels to reflect therapies that increase or replace expression of genetic defects, analysis of the genetic networks of normal gene expression that might be affected by manipulating this pathway, and tests for effects of feedback regulation within the proposed network architecture.